Members of the Enterobacteriaceae family of Gram-negative bacteria are among the most common food-borne and hospital acquired pathogens. These organisms have had a huge impact upon human history by causing devastating diseases, such as the black plague and typhoid fever, as well as more common urinary tract infections, dysentery and hospital acquired infections. Many members of the Enterobacteriaceae are well known for acquiring antibiotic resistance, including pan-resistant strains of Klebsiella pneumoniae, and carbapenem-resistant Escherichia coli and Serratia marcescens. The discovery of the ndm-1 carbapenemase has underscored the need to identify novel antibiotics.
Bacteria can gain resistance through acquisition of additional DNA from a plasmid or other source, mutation of an antibiotic target site or a transporter protein, or other genetic mechanism. However, most bacteria can also gain antibiotic tolerance through formation of a biofilm. Cells in a biofilm are up to 1000 times more tolerant to antibiotics and disinfectants compared to their planktonic counterparts. Thus, deleterious biofilms cause serious problems such as chronic infections in humans, as well as persistent corrosion and equipment failure in industry. Although mechanisms by which bacteria in biofilms resist killing by antibiotics are not completely elucidated, several mechanisms have been postulated. Pseudomonas aeruginosa has two different active mechanisms by which biofilms gain antibiotic tolerance. In one of these, periplasmic cyclic glucans are produced in biofilm cells that bind to aminoglycosides. Another mechanism is the modification of the lipid A component of lipopolysaccharide in response to extracellular DNA found in a biofilm, resulting in diminished activity of antimicrobial peptides. In both of these examples, differential gene expression in the biofilm leads to reduced antibiotic susceptibility. Other mechanisms by which biofilms resist antibiotic activity include the presence of “persister” cells, microenvironments within the biofilm that prevent the antibiotic from working, and inhibition of antibiotic access to bacteria within a biofilm. There is therefore a continued need for new antibiotics, particularly antibiotics that are effective against established biofilms.